m03 pdf 2.3 luis veloso
DESCRIPTION
Clinical Trial documentation presentationTRANSCRIPT
Clinical Trial
Documentation
CHAIRPERSON
Helena Beaumont, BSc
WORKSHOP #02
13-12-2012 M03 1
Clinical Trial Report
Luís Veloso, BSc
Medical Writing Unit, Eurotrials
2.3
Describe basic concepts and practical aspects
related to the planning and structuring of Clinical
Trial/Study Reports.
Objective
Clinical Study Report
“an integrated full report of an individual study of any therapeutic,
prophylactic or diagnostic agent conducted in patients, in which the clinical
and statistical description presentations, and analyses are integrated into a
single report, incorporating tables and figures into the main text of the
report, or at the end of the text, and with appendices…”
Clinical Study Report (CSR) - Definition
Reference: CPMP/ICH. 137/95. ICH topic E3. Structure and Content
of Clinical Study Reports. London: European Medicines Agency; 1996.
“The integrated full report of a study should not be derived by simply joining a separate clinical and statistical report”
• CSRs tell the full “story” of a trial
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CSR Definition
Scientific Publication (e.g. CSR)
How it was carried out?
Why the trial was conducted? 1. Introduction/Rationale
2. Objectives
3. Methodology
4. Ethical and Regulatory considerations
5. Results
6. Discussion/Conclusion
What was observed?
What do these findings mean?
Why CSRs are required?
Clinical Study Report is the masterpiece of a marketing authorization application, as it represents the integrated full report of efficacy and safety data for an individual study of a therapeutic or diagnostic agent
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CSR Purpose
Efficacy and safety pivotal clinical trials and human pharmacology investigations
• proposed indication • support information included in product labeling
Contribute
CSR
Reported as
CSRs constitute one module of the Common Technical Document (CTD)
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• CSRs are included in CTD
• CTD is a common format for the organization of technical reports for submissions to regulatory authorities
• CTD is organized in 5 Modules
• CSR is included in Module 5
CSR as part of CTD
Reference: Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use - M4. Current Step 4 version, dated January 13, 2004
Placement of CSRs within CTD structure
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CSR as part of CTD
5.3.5 – Indication Z
5.3.5.1 - Study Reports of Controlled Clinical Trials Pertinent to the Claimed Indication
5.3.5.1.1 - Indication Z - Placebo Controlled Trials
5.3.5.1.2 - Indication Z - Active Controlled Trials
Study XXX - Integrated CSR
Study YYY - Integrated CSR…
5.3.5 – Indication Q
5.3.5.1 - Study Reports of Controlled Clinical Trials Pertinent to the Claimed Indication
5.3.5.1.1 - Indication Q - Placebo Controlled Trials
5.3.5.1.2 - Indication Q - Active Controlled Trials
Study ZZZ - Integrated CSR…
Study FFF - Integrated CSR
CTDs have strict formatting and layout requirements for documents
• Margins that allow printing on both A4 and 8.5 x 11” (Letter Size US) paper
• Fonts for text and tables should be of a style and size that are large enough to be easily legible, even after photocopying - Times New Roman, 12-point font is recommended for narrative text.
• References should be cited in accordance with the current edition of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, International Committee of Medical Journal Editors (ICMJE)
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CSR as part of CTD
Also impacts on CSR formatting and layout
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[Sponsor]
CSR as part of CTD
CSR as part of electronic CTD (eCTD)
- Up until recently regulatory applications to Health Authorities were paper-based.
- In 2005 Medicine Agencies agreed to receive electronic-only submissions (eCTD) starting from the end of 2009.
- A transition period when a mixed process could be followed (Non-eCTD electronic submissions - NeeS) until full adoption of eCTD.
- From 1st January 2012 new market applications would only be accepted in
eCTD format (Portugal)
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CSR as part of eCTD
Electronic format submissions involve additional requisites comparing to paper.
- Granularity (one document = one e-file [PDF])
- e-file placing and naming conventions
- PDF conversion (size, dots per inches when scanned)
- Navigational aids (bookmarks and hypertext links).
Guidance for Industry on Providing Regulatory Information in Electronic Format:
eCTD electronic Submissions, Version 1, may 2009
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Use of word macros Use of PDF software that allow legibility
with Acrobat Reader (v5.0 or higher) Facilitate compliance!
Structure of full-integrated CSR
CSR Structure
Appendix 16.1
Appendix 16.2
Appendix 16.3
Appendix 16.4
Reference: CPMP/ICH. 137/95. ICH topic E3. Structure and Content
of Clinical Study Reports. London: European Medicines Agency; 1996.
Core CSR +
Structure of Full-integrated CSR
CSR Structure - Core
1. TITLE PAGE 2. SYNOPSIS 3. TABLE OF CONTENTS 4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 5. ETHICS 6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 7. INTRODUCTION 8. STUDY OBJECTIVES 9. INVESTIGATIONAL PLAN (Design, Treatments, Variables, Quality Assurance, Statistical Methods and Changes in Study Conduct) 10. STUDY PATIENTS 11. EFFICACY EVALUATION 12. SAFETY EVALUATION 13. DISCUSSION AND OVERALL CONCLUSIONS 14. END-OF-TEXT TABLES AND FIGURES 15. REFERENCE LIST 16. APPENDICES
Core CSR
(Body of
report)
CSR Structure - Core
Original plan
Differences from original plan
Interpretation
Findings
Background/Rationale
CSR CONTENT
Objectives
Investigational Plan
Changes in study conduct and analyses
Study Patients
Discussion & Overall Conclusions
Efficacy Evaluation
Safety Evaluation
CSR Structure - Core
Current version of Study Protocol
MAIN SOURCES OF INFORMATION
Protocol Amendments
Statistical Analysis Plan (SAP)
Project management-related
Statistical Output/Report
Patient data listings
Statistical Output End-of-text tables and Figures
Original plan
Differences from original plan
Interpretation
Findings
Relevant literature
CSR Structure – Statistical Outputs
Statistical outputs (examples)
Patient Disposition Adverse Events
Efficacy
CSR Structure – Statistical Outputs
Statistical outputs (examples)
Help!... I need support from Statistician for interpretation of results!
Appendix 16.1
Appendix 16.2
Appendix 16.3
Appendix 16.4
Study information Protocol/amendments, CRF, List IECs, Investigators (CVs), medication batches used, Randomizations
codes, SAP, etc.
Patient Data Listings Discontinued patients, Protocol deviations,
Demographic data, etc.
Case Report Forms (Deaths, SAEs, AE withdrawals)
CSR Structure - Appendices
Individual Patient Data Listings (US)
Note for guidance on the inclusion of appendices to clinical study reports in Marketing
Authorisation Applications. CHMP/EWP/2998/03/Final, 23 June 2004
Patient Data Listings – Appendix 16.2 (Example)
Data listings are those needed to support critical analyses
CSR Structure - Appendices
CSR writing challenges
Some aspects/sections of CSR are more challenging than others
Section 9. Investigational plan: 9.2 - Discussion of Study Design, including the choice of Control Groups
9.5.2 - Appropriateness of Efficacy and Safety measurements
Both aspects are often absent from study protocols requiring discussion with protocol authors
CSR writing challenges
Section 9. Investigational plan: 9.8 Changes in the Conduct of the Study or Planned Analyses
The narrative in CSR should explain the implications of the changes in the interpretation of results.
Changes in study conduct:
- e.g. Waivers/Exemptions for non-eligible patients, or any procedure conducted differently from study protocol at the site level.
Changes in planned analysis:
- e.g. Insufficient data to analyze a secondary endpoint
There are changes that are not previoulsy documented in formal documents (e.g., Amendments) - exhaustive searching will be required from the Medical Writer
CSR writing challenges
Section 10. Study Patients:
- Disposition of Patients
- Protocol deviations
Review of Patient Data Listings is sometimes required to obtain a clear picture of patients disposition
CSR writing challenges
Section 11. Efficacy evaluation:
Section 12. Safety evaluation:
• Description of results discussed with Statistician
• Balance between tables, graphs and listings presentation vs narrative text
Section 13. Efficacy, Safety discussion
”…Depending on the nature and importance of such studies, a less detailed
report might be appropriate.
Abbreviated CSR or a Synopsis
Safety emphasis
- ICH topic E3 is not very specific about the
content of Abbreviated CSR
CSR - Abbreviated
Reference: FDA - Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER).
Guidance for Industry: submission of abbreviated reports and synopses in support of marketing applications. Rockville (MD):
Department of Health and Human Services, Food and Drug Administration, Center for mDrug Evaluation and Research; 1999.
Reference: CPMP/ICH. 137/95. ICH topic E3. Structure and Content
of Clinical Study Reports. London: European Medicines Agency; 1996.
- A guideline by the Food and Drug Administration (1999) is the only document available from a regulatory authority that recommends which sections can be included in an abbreviated CSR.
Q:Every clinical trial needs a full-lenght CSR? R: No
• uncontrolled studies or other studies not designed to establish efficacy • seriously flawed or aborted studies. • controlled studies that examine conditions clearly unrelated to those for which a
claim is made.
Full description of safety aspects
Reference: CPMP/ICH. 137/95. ICH topic E3. Structure and Content
of Clinical Study Reports. London: European Medicines Agency; 1996.
Key Message: Any question regarding whether full integrated CSR are needed consult the reviewing health authorities.
Under which circumstances may an Abbreviated CSR be submitted?
CSR - Abbreviated
Multidisciplinary activity
QUALITY ASSURANCE Audit to integrated CSR
TRIAL PROJECT MANAGER Project history Documentation Appendices
CSR - Planning the Writing
CLINICAL EXPERT Data review Clinical narratives Discussion of results
STATISTICIAN SAP Statistical outputs Results Interpretation
REGULATORY AFFAIRS Liaison with reviewing
authorities Technical input (eCTD)
DATA MANAGER Data Listings
MEDICAL WRITER (Primary author)
CSR PROJECT MANAGER
Liaison all parties
Kick-off meeting
Mock or Shell CSR 1st Draft CSR 2nd Draft CSR
• Timelines
• Parties involved
• Review flow
The writing steps for a full lenght CSR
• Plan
(derived from Protocol)
• Shells for results
(sample text, tables,
figures, listings)
• Plan (robust)
• Results (with text,
tables, figures,
listings)
Compilation of Appendices
• Plan (finalized)
• Results
(robust)
• Discussion
drafted
Final CSR
• Core CSR
• Integration of
Appendices
Technical Release of CSR Performed by Regulatory Affairs personnel
CSR - Planning the Writing
CSR 1st draft
CSR 2nd draft
Final CSR (Medical Writer)
MOCK
Compilation of Appendices
Statistics involvement
Data Management involvement
CSR - Planning the Writing Chronology of events:
How long it takes to prepare CSR? Depends on the study’s complexity: - No of patients - Study Phase - Indication - Nr of secondary efficacy variables - Complexity of Statistical Analysis
Sam Hamilton. Effective scheduling of Clinical Study Reports,
The Write Stuff, The Journal of the European Medical Writers Association.
Vol. 17, No. 3, 2008
For a moderate complexity CSR : • Phase 3 study • 200–400 subjects • 6 to 12 twelve secondary efficacy variables • some complex statistical analysis
80 working days (average)
CSR - Planning the Writing
CSR are complex and multi-component document so for an adequate planning the Primary Author should have a deep knowledge of: CSR requisites (structure, content and formatting)
Different disciplines involved, respective tasks and timings
Final Remarks
OBRIGADO
QUESTÕES?